Pre-malignant pancreatic cysts that are difficult to characterize and treat are increasingly discovered in the US over the last two decades due to advances in imaging and an aging population. With the incidence of highly lethal pancreatic cancer rising in the US, intervening on pancreatic cysts with malignant potential in a safe and effective way is a major public health concern. While patients have been historically limited to radiographic surveillance or potentially hazardous surgery as undesirable methods of managing these cysts, endoscopic ultrasound guided fine needle injection (EUS-FNI) has emerged as a less-invasive, safe and effective method of early intervention. For EUS-guided treatment of pancreatic cysts today, care typically includes lavage with ethanol. However, experts agree that adverse events (AEs) observed during treatment are due to ethanol use. Recently, based on the safety concerns surrounding ethanol use, as well as the promising treatment findings linked to the infusion of paclitaxel, our team created an ethanol-free (EF), combination chemotherapy treatment consisting of an admixture—paclitaxel and gemcitabine—specifically designed to target pancreatic cystic neoplasia by EUS-guided injection. Our team completed testing of this novel treatment strategy in 2017 as a preliminary randomized trial, showing that EF lavage (i.e., saline) with combination chemotherapy was as effective, and far safer, than the same chemotherapy treatment with the inclusion of ethanol lavage (EL). In this proposal, our aim is increase the scale of our pilot study, conducting a large and definitive multi-center trial that will be the first funded RCT to compare treatment with EL to ethanol-free (EF) treatment with combination infusion of chemotherapeutic agents. All subjects will have qualifying cystic lesions aspirated and evacuated, and undergo a follow-up procedure at 3 months and final imaging at 12 months. We will randomly assign 100 adult patients with pancreatic cysts to two study arms: (1) Ethanol lavage (EL): EL, followed by infusion of a paclitaxel-gemcitabine admixture, or (2) Ethanol Free (EF): saline lavage, followed by infusion of the same paclitaxel-gemcitabine admixture. We hypothesize that EF treatment will result in significantly fewer adverse events and will have complete cyst ablation resolution rates that are not inferior to EL treatment. If the EF intervention proves to be non-inferior to, and significantly safer than, treatment with EL, it will validate EUS-FNI as a viable treatment modality for intervening on pre-malignant cysts and will change the standard of care for pancreatic cyst management. Critically, if EF treatment is successful, it may alter the treatment decisions that patients make and change the treatment options that centers of excellence offer.